PROJECT SUMMARY/ABSTRACT Prevalence of saccular intracranial aneurysms (IA) in western populations is estimated at around ~3%. Clinically, IA present a dilemma, in that they are usually asymptomatic; however, IA are extremely dangerous if they rupture, causing subarachnoid hemorrhage (~50% mortality). There is convincing evidence that continued IA growth increases the risk of rupture (12-24 times). To better monitor and predict IA progression, there is a compelling need to better understand clinical IA growth (aneurysmal remodeling). 90% of IA occur within the arteries of the Circle of Willis (CoW). Despite there being overwhelming evidence connecting CoW vascular remodeling and IA disease, the majority of IA research focuses only on the IA site, and does not consider the contribution of connected arteries. Specific vascular remodeling in the CoW arteries may provide an additional indicator for monitoring IA progression. The biochemical processes that occur at the IA site include inflammation and extracellular matrix remodeling leading to cell death and vessel wall degeneration. Analyses in animal models have strongly connected arterial wall shear stress (WSS) as a trigger of these processes, leading to IA initiation and remodeling. Patient-oriented research has further linked areas of low WSS with IA growth. Because CoW vasculature can change during IA growth, the blood flow entering IA changes and may create a new level of WSS to stabilize the remodeling process. Better understanding how human IA may naturally stabilize is highly relevant to predicting IA progression, and the role of changing WSS will be investigated in this grant. In our recent study of 520 clinically monitored IA, we found that while many IA grew consistently, following a projected growth path, others became stable. We also found that IA growth speed is significantly faster in women. Given the association of IA with sex, family history, and disease, different patterns of vascular remodeling may occur within groups with different genetics or medical history. We propose a clinical translational study to study IA growth in different genetic and medical history groups. We hypothesize IA growth may associate with patterns of vascular remodeling within the CoW. We will test our hypothesis with the following specific aims: (1) Is IA growth a local phenomenon or it associated with vascular remodeling within the CoW? (2) Do genetically similar individuals undergo similar patterns of vascular remodeling? (3) Does blood flow within the CoW associate with vascular remodeling? By identifying how IA disease progression may associate with other remodeling within the CoW, this study can identify new imaging biomarkers that enable improved IA treatment decisions. This proposal is significant because there is an unmet need to accurately assess IA disease progression and changes in risk. This proposal is innovative because it will extend existing IA studies to include more, relevant cerebrovascular arteries and longitudinal data, while implementing several technical innovations specific to this problem which can translate to clinical tracking of cerebrovascular changes